This study examined the familial transmission of anxiety disorders and substance abuse using a combination of the family study/longitudinal high risk paradigms. This study also investigated comorbidity between physical disorders and mood and anxiety disorders. The chief findings reveal specificity of familial aggregation of anxiety disorders in general and the panic and social phobia subtypes in particular. Likewise, there was familial aggregation of substance abuse, with some suggestion of specificity of specific drugs. In contrast, although there was no evidence for vertical transmission of nicotine dependence, there was an increased risk of nicotine dependence among siblings. With respect to physical disorders, it was found that anxiety disorders were most strongly associated with physical disorders in general, and that there was evidence for co-transmission of migraine with anxiety and mood disorders in families. A 10-year prospective study of the offspring of parents with these conditions was conducted in order to identify the early signs and manifestations of parental disorders. A comprehensive domain of assessments of individual, familial and social risk factors among the offspring of affected and control parents was employed. The results reveal that there was specificity of expression of anxiety disorders in youth; by contrast, behavior disorders were more strongly associated with parental psychopathology and disrupted home environments in general than with specific parental disorders. Numerous abnormalities in the indirect measures of brain functioning also discriminated between offspring of parents with anxiety disorders and substance abuse, as well as children with attention deficit disorder. These findings are consistent with a congenital/developmental basis for their vulnerability to these conditions. We have continued to analyze this rich data set at the NIMH where we have also made substantial progress in defining the factors involved in the transmission of these conditions in families. These data have provided a valuable resource for trainees in our laboratory who have learned to analyze data on familial aggregation as we await the results of the ongoing studies in our research group. The results of the recent analyses have been used to refine the research questions and methods of the current NIMH family study that we describe below. The following findings have guided the development of our research. First, we found a syndromic association between mania and migraine with specificity of familial transmission (Merikangas et al, under review). Second, we found a strong within person association between migraine and panic disorder, but there was no familial association between these two conditions (Merikangas et al, under review). Third, we found differential rates of familial aggregation among probands recruited from clinical compared to community settings (Low et al, under review). Fourth, we found that there is specificity of familial transmission of panic and social anxiety disorders, and demonstrate that the association between these disorders in probands and relatives is not attributable to comorbid mood, anxiety or substance use disorders. Therefore, despite the high magnitude of co-occurrence of panic disorder and social anxiety, there are distinct etiologic factors underlying each disorder. Fifth, we found that there is a high magnitude of spousal concordance for substance use disorders and in contrast, no concordance for anxiety disorders. Couples were also concordant for the absence of disorders. Concordance for mental disorders is associated with poorer global functioning and persistent illness among probands. The most likely mechanism for spouse concordance is primary assortative mating for the disorder or its correlates. Sixth, we found that the increased frequency of migraine in women in is not attributable to genetic factors; therefore, the increased exposure to non-familial endogenous or exogenous risk factors for migraine that lower the threshold for expression of migraine in women.